Zebrafish regenerate full thickness optic nerve myelin after demyelination, but this fails with increasing age.
Zebrafish regenerate full thickness optic nerve myelin after demyelination, but this fails with increasing age.
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DOI：
10.1186/s40478-014-0077-y
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发表时间：
2014-07-15
影响因子：
7.1
通讯作者：
Williams A
中科院分区：
文献类型：
--
作者：
Münzel EJ;Becker CG;Becker T;Williams A
在人类脱髓鞘中枢神经系统（CNS）疾病多发性硬化症中，髓鞘再生促进恢复并限制神经退行性变，但这是低效的，最终总是失败。此外，这些再生的髓鞘比原来的更薄更短，使下面的轴突潜在地脆弱。在啮齿动物模型中，CNS髓鞘再生更有效，因此在年轻动物（但不是老年动物）中，有髓鞘轴突的数量有效地恢复到正常，但在年轻和老年啮齿动物中，再生的髓鞘仍然短而薄。髓鞘再生效率的这些差异的原因，与发育髓鞘相比，更薄的髓鞘再生髓鞘和随后对下面的轴突的影响尚不清楚。我们研究了高度再生的成年斑马鱼（Danio rerio）的CNS髓鞘再生，以更好地理解我们假设的高效髓鞘再生机制，并确定与哺乳动物CNS髓鞘再生的差异，因为斑马鱼幼虫越来越多地用于高通量筛选，以确定潜在的药物靶点，以改善髓鞘形成和髓鞘再生。我们开发了一种新的方法，在成年斑马鱼视神经中诱导局灶性脱髓鞘病变，而没有明显的轴突损伤，并描述了细胞随时间的变化。在年轻和年老的成年斑马鱼视神经中，再髓鞘形成确实是有效的，并且在脱髓鞘后4周，有髓鞘轴突的数量恢复到正常，但是节间长度短。然而，与啮齿动物或人类不同，年轻斑马鱼的这些再生髓鞘具有正常厚度，而老年斑马鱼的髓鞘很薄，甚至在3个月后仍然如此。随着年龄的增长，在髓鞘再生中无法恢复正常的髓鞘厚度与巨噬细胞/小胶质细胞反应减少有关。与哺乳动物不同，斑马鱼能够在脱髓鞘后有效地恢复视神经轴突周围正常厚度的髓鞘。然而，随着年龄的增长，当只实现薄髓鞘时，这就失败了。这为我们提供了一个新的模型，尝试和解剖的机制，恢复髓鞘厚度在中枢神经系统髓鞘再生。本文的在线版本（doi：10.1186/s40478-014-0077-y）包含补充材料，可供授权用户使用。
In the human demyelinating central nervous system (CNS) disease multiple sclerosis, remyelination promotes recovery and limits neurodegeneration, but this is inefficient and always ultimately fails. Furthermore, these regenerated myelin sheaths are thinner and shorter than the original, leaving the underlying axons potentially vulnerable. In rodent models, CNS remyelination is more efficient, so that in young animals (but not old) the number of myelinated axons is efficiently restored to normal, but in both young and old rodents, regenerated myelin sheaths are still short and thin. The reasons for these differences in remyelination efficiency, the thinner remyelinated myelin sheaths compared to developmental myelin and the subsequent effect on the underlying axon are unclear. We studied CNS remyelination in the highly regenerative adult zebrafish (Danio rerio), to better understand mechanisms of what we hypothesised would be highly efficient remyelination, and to identify differences to mammalian CNS remyelination, as larval zebrafish are increasingly used for high throughput screens to identify potential drug targets to improve myelination and remyelination. We developed a novel method to induce a focal demyelinating lesion in adult zebrafish optic nerve with no discernible axonal damage, and describe the cellular changes over time. Remyelination is indeed efficient in both young and old adult zebrafish optic nerves, and at 4 weeks after demyelination, the number of myelinated axons is restored to normal, but internode lengths are short. However, unlike in rodents or in humans, in young zebrafish these regenerated myelin sheaths were of normal thickness, whereas in aged zebrafish, they were thin, and remained so even 3 months later. This inability to restore normal myelin thickness in remyelination with age was associated with a reduced macrophage/microglial response. Zebrafish are able to efficiently restore normal thickness myelin around optic nerve axons after demyelination, unlike in mammals. However, this fails with age, when only thin myelin is achieved. This gives us a novel model to try and dissect the mechanism for restoring myelin thickness in CNS remyelination. The online version of this article (doi:10.1186/s40478-014-0077-y) contains supplementary material, which is available to authorized users.
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影响因子：
16.2
作者：
Brinkmann, Bastian G.;Agarwal, Amit;Sereda, Michael W.;Garratt, Alistair N.;Mueller, Thomas;Wende, Hagen;Stassart, Ruth M.;Nawaz, Schanila;Humml, Christian;Velanac, Viktorija;Radyushkin, Konstantin;Goebbels, Sandra;Fischer, Tobias M.;Franklin, Robin J.;Lai, Cary;Ehrenreich, Hannelore;Birchmeier, Carmen;Schwab, Markus H.;Nave, Klaus Armin
通讯作者：
Nave, Klaus Armin
影响因子：
64.8
作者：
Fuenfschilling, Ursula;Supplie, Lotti M.;Mahad, Don;Boretius, Susann;Saab, Aiman S.;Edgar, Julia;Brinkmann, Bastian G.;Kassmann, Celia M.;Tzvetanova, Iva D.;Moebius, Wiebke;Diaz, Francisca;Meijer, Dies;Suter, Ueli;Hamprecht, Bernd;Sereda, Michael W.;Moraes, Carlos T.;Frahm, Jens;Goebbels, Sandra;Nave, Klaus-Armin
通讯作者：
Nave, Klaus-Armin
影响因子：
12.7
作者：
Boyd A;Zhang H;Williams A
通讯作者：
Williams A
影响因子：
11.2
作者：
Harrington, Emily P.;Zhao, Chao;Fancy, Stephen P. J.;Kaing, Sovann;Franklin, Robin J. M.;Rowitch, David H.
通讯作者：
Rowitch, David H.
影响因子：
4.7
作者：
Buckley, Clare E.;Marguerie, Anita;Franklin, Robin J. M.
通讯作者：
Franklin, Robin J. M.